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Polymorphic α-Glucans as Structural Scaffolds in Cryptococcus Cell Walls for Chitin, Capsule, and Melanin: Insights From 13C and 1H Solid-State NMR
Full text linkCryptococcus species are major fungal pathogens responsible for life-threatening infections in approximately a million individuals globally each year, with alarmingly high mortality rates. These fungi are distinguished by a distinctive cell wall architecture further reinforced by two virulence-associated layers, melanin and capsule, rendering them insensitive to antifungal agents targeting the cell wall, such as echinocandins. The molecular interplay between these three biomolecular layers remains poorly understood. Here we employ solid-state NMR spectroscopy to examine intact cells of both wild-type and capsule-deficient strains of C. neoformans, along with melanized cells. High-resolution 13C and 1H data revealed five distinct structural forms of α-1,3-glucans that play versatile roles in forming the rigid cell wall scaffold by interacting with chitin microfibrils and chitosan, and in stabilizing the mobile matrix by associating with β-1,6-glucan and a small fraction of β-1,3-glucan. Two primary forms of α-1,3-glucans were distributed throughout the cell wall, hosting melanin deposition in the inner domain and capsule attachment on the cell surface. These findings offer a paradigm shift in understanding the cryptococcal cell wall and its interaction with two key virulence factors on opposite sides, raising critical biochemical questions that could inform the development of more effective antifungal treatments for cryptococcosis
Whole-Exome Sequencing Identified Molecular Variants Linked to the Progression of Gastric Precancerous Lesions in Patients from Southwestern Colombia—An Exploratory Approach.
Full text linkQualitative insights into drug use safety strategies and social support among sexual minority women who inject drugs in Baltimore, Maryland
Full text linkBackground: Sexual minority women (SMW) experience higher rates of substance use relative to heterosexual women in the U.S. but remain an under-studied population. SMW who inject drugs (SMWWID) navigate an unpredictable drug market and may experience complex relationships within their social spheres. We explore cisgender SMWWID’s strategies to maintain safety while injecting drugs, and the influence of their social support systems on those strategies. Methods: We conducted N = 16 phone-based, semi-structured, in-depth interviews with SMWWID in Baltimore, Maryland between June-October 2021. The interviews explored participants’ sexual orientation and gender identities, social networks and support systems, drug use behaviors and HIV risk, and experiences accessing services. Using an inductive thematic analysis approach, we examined emergent themes related to drug use, social support, safety, and HIV and identified key safety strategies and social support experiences for SMWWID. Results: SMWWID employed various strategies to “stay safe,” which they primarily interpreted as ensuring overdose safety (i.e., using drugs in the presence of others, carrying Naloxone, purchasing strategies), and additionally as infectious disease safety (i.e., avoiding syringe sharing, using sterile syringes) and avoiding threats of violence (i.e., maintaining situational awareness while using drugs). Romantic or sexual partners, family and friends, and the wider community were sources of social support for overdose safety, and family and friends also provided material support (e.g., financial, housing). Syringe sharing with romantic partners and threats of violence from people in the community detracted from SMWWID’s safety. Conclusion: SMWWID in this sample reported strong safety prioritization while using drugs, often facilitated by their social support systems. Harm reduction interventions that consider SMWWID’s relationships, including those that aim to improve social connectedness, may better meet the needs of SMWWID, thereby enhancing safety
Real-world treatment patterns and management gaps of lumbar disc herniation in the United States
Full text linkBACKGROUND: Lumbar disc herniation (LDH) affects approximately 1% to 3% of the population annually and leads to substantial physical burden, quality-of-life burden, and productivity loss. Commonly used interventions, including pharmacological and epidural steroid injections (ESIs), have limited high-quality evidence to support their effectiveness in the long-term for treating LDH beyond symptom relief. In general, there is a lack of consensus for timing of treatment after LDH onset and limited data on real-world treatment of LDH. The objective of this study was to describe current real-world treatment patterns and inform gaps in clinical management of patients with LDH. METHODS: A retrospective analysis was performed using data from January 01, 2018 through March 31, 2023 of a United States commercial health insurance claims database (IQVIA PharMetrics Plus). Patients aged 30-70 years with newly-diagnosed LDH and continuous insurance enrollment for ≥6 months before and ≥12 months after index (first) LDH diagnosis were included. Relevant billing codes were used to identify LDH, related treatments (nonpharmacologic, pharmacologic, invasive), and comorbidities. Demographic and clinical characteristics were summarized for the baseline (preindex) period. Treatment patterns were described over the follow-up period, up to 3 years after LDH diagnosis. Time from LDH diagnosis to ESI(s) and surgery(ies) were calculated. RESULTS: A total of 1,086,552 patients with LDH were included, with a mean age of 50.8 years. Patients had a mean follow-up of 27 months after LDH diagnosis. Nearly 20% of patients with LDH underwent ESI, with half of this group undergoing multiple ESIs. Multiple ESIs were associated with a greater likelihood of surgical intervention and repeat surgical intervention compared to those who only underwent single ESI. LDH surgery was performed on 7.2% of patients, approximately 10% of whom had multiple surgeries during follow-up. A large subset (44.1%) of patients who underwent LDH surgery did not have any ESI prior to surgery. General limitations of claims data analyses can include data misclassification, missing claims for diagnoses and procedures that were conducted, missing clinical information (severity of condition, insights into clinical decision making), and some missing patient demographics and characteristics. CONCLUSIONS: In this study, approximately one quarter of patients with LDH underwent ESI and/or surgery after conservative treatment. Opportunities exist to provide more guideline-concordant care to patients with LDH. In addition, unmet needs exist in the current treatment options for patients with LDH, potentially including the need for other nonsurgical treatment options for patients who do not fully respond to conservative treatment
IFI16 Mediates Deacetylation of KSHV Chromatin via Interaction with NuRD and Sin3A Co-Repressor Complexes
Full text linkIFI16 is a well-characterized nuclear innate immune DNA sensor that detects foreign dsDNA, including herpesviral genomes, to activate the inflammasome and interferon pathways. Beyond immune signaling, IFI16 also functions as an antiviral restriction factor, promoting the silencing of invading viral genes through transcriptional and epigenetic mechanisms. We recently demonstrated another role of IFI16, in which it interacts with and recruits the class I histone deacetylases, HDAC1 and 2, to the KSHV latency protein LANA, modulating its acetylation and function. In this study, we asked whether these IFI16-HDAC1/2 interactions contribute to broader epigenetic regulation of the KSHV chromatin. Our findings reveal that IFI16 associates with and facilitates the recruitment of the NuRD and Sin3A co-repressor complexes-both multiprotein, HDAC1/2-containing chromatin regulators-on KSHV episomes. Depletion of IFI16 led to reductions in NuRD and Sin3A occupancy on viral chromatin, accompanied by increased histone acetylation at lytic gene promoters. These results suggest that IFI16 plays a critical role in recruiting or stabilizing these HDAC-containing co-repressor complexes on the KSHV genome, thereby enforcing transcriptional silencing of lytic genes and maintaining latency in KSHV. Our study expands the known functions of IFI16 and identifies a novel epigenetic mechanism by which it modulates herpesviral chromatin states
The Dual-Port Approach to the Posterior Incisura: A Quantitative Cadaver Study of a Combined Endoscopic Paramedian Supracerebellar Infratentorial and Occipital Interhemispheric Transtentorial Approach
No full textBACKGROUND: The posterior incisura is a deep and surgically challenging area with complex neurovasculature. Endoscopic paramedian supracerebellar infratentorial approaches (EPSCITAs) have improved access and visualization of this region. However, endoscope and instrument conflict within this deep and narrow corridor remains a key limitation. This study evaluates the feasibility of a combined EPSCITA and endoscopic occipital interhemispheric transtentorial approach (EOIHTTA) with the aim of improving surgical freedom and visualization in this region. METHODS: Five embalmed and latex-injected cadaveric donors were dissected bilaterally (10 sides total). Measurements were taken at the EPSCITA port and then were repeated after addition of the EOIHTTA port. Measurements of surgical freedom at 3 anatomic targets, area of exposure, distance to the pineal gland, and angle at approach port, were obtained using stereotactic navigation. Statistical analyses were performed using 2-sample t-tests. RESULTS: Addition of the EOIHTTA port improved the vertical angle of approach from 15.07° to 58.96°, P \u3c 0.0001, and horizontal angle of approach from 28.1° to 50.02°, P \u3c 0.0001. The area of surgical freedom at each anatomic target increased notably, with the area at the pineal gland expanding from 663 mm to 1042 mm, P \u3c 0.005, the superior colliculus from 806 mm to 1090 mm, P \u3c 0.005, and the splenium from 415 mm to 902 mm, P \u3c 0.005. CONCLUSIONS: This dual-port approach enhances access to the posterior incisura, providing improved surgical exposure and maneuverability while reducing instrument conflict. This technique is an effective minimally invasive approach to this deep-seated region, addressing the limitations of traditional single-port techniques
ADAM17 Supports Disinhibition of Pre-sympathetic Glutamatergic Neurons Through Microglial Chemotaxis
No full textA disintegrin and metalloprotease 17 (ADAM17) is a membrane-bound enzyme that cleaves cell-surface proteins. Here, we discovered that neuronal ADAM17-mediated signaling supports the reduction of inhibitory presynaptic inputs to the pre-sympathetic glutamatergic neural hub, located in the paraventricular nucleus of the hypothalamus (PVN), upon stimulation by angiotensin II (Ang-II). For Ang-II-induced disinhibition, targeting microglial migration had an effect similar to ADAM17 knockout in glutamatergic neurons. Ang-II promoted neuron-mediated chemotaxis of microglia via neuronal CX3CL1 and ADAM17. Inhibiting microglial chemotaxis by targeting CX3CR1 abolished the Ang-II-induced microglial displacement of GABAergic presynaptic terminals and significantly blunted Ang-II’s pressor response. Using conditional and targeted knockout models of ADAM17, an increase in the contact between pre-sympathetic neurons and reactive microglia in the PVN was demonstrated to be neuronal ADAM17-dependent during the developmental stage of salt-sensitive hypertension. Collectively, this study provides evidence that neuronal ADAM17-mediated microglial chemotaxis facilitates the disinhibition of pre-sympathetic glutamatergic tone upon hormonal stimulation
Prior adolescent oxycodone exposure enhances pain sensitivity following chronic intermittent ethanol in adult female mice
Full text linkThe opioid crisis remains a critical public health concern, with rising rates of overdose and opioid use disorder. While opioids are effective for managing pain, both chronic use and withdrawal are associated with increased pain sensitivity. Although most prior research has focused on adults, opioid use during adolescence is common and linked to a heightened risk for developing alcohol use disorder and other forms of substance misuse. Like opioids, acute alcohol use can be analgesic, but chronic alcohol exposure and withdrawal lead to increased pain sensitivity. However, the interactive effects of adolescent opioid and adult alcohol exposure on pain remain poorly understood. In this study, we investigated whether adolescent oxycodone exposure (AOE) alters the development of mechanical and thermal sensitivity following adult chronic intermittent ethanol (CIE) vapor exposure in male and female mice. AOE alone induced transient mechanical but not thermal hypersensitivity in both sexes, which resolved within six days of cessation. In adulthood, CIE exposure induced mechanical and thermal hypersensitivity in both sexes. Importantly, a prior history of AOE prolonged CIE-induced hypersensitivity in female, but not male mice. Additionally, females with combined AOE and CIE exposure exhibited enhanced hypersensitivity in the Randall–Selitto test compared to all other groups. These findings demonstrate that AOE increases vulnerability to pain-related effects of adult CIE exposure in females. This work highlights the importance of studying poly-drug interactions across developmental windows and underscores the need to include both sexes in preclinical models of pain and substance use
Integrated Systems Biology Identifies Disruptions in Mitochondrial Function and Metabolism as Key Contributors to HFpEF
Full text linkHeart failure with preserved ejection fraction (HFpEF) accounts for ∼50% of HF cases. The ZSF1-obese rat model recapitulates clinical features of HFpEF including hypertension, obesity, metabolic syndrome, exercise intolerance, and diastolic dysfunction. We utilized a systems-biology approach to define the metabolic and transcriptional signatures to gain mechanistic insight into pathways contributing to HFpEF development. Male ZSF1-obese, ZSF1-lean hypertensive controls, and WKY (wild-type) controls were compared at 14 weeks of age for extensive physiological phenotyping and left ventricle (LV) tissue harvesting for unbiased-metabolomics, RNA-sequencing, and mitochondrial morphology and function. Utilizing ZSF1-lean and WKY controls enabled a distinction between hypertension-driven molecular changes driving HFpEF pathology, versus hypertension + metabolic syndrome. Comparison of ZSF1-lean vs WKY (ie, hypertension-exclusive effects) revealed metabolic remodeling suggesting increased aerobic glycolysis, decreased β-oxidation, and dysregulated purine and pyrimidine metabolism with few transcriptional changes. ZSF1-obese rats displayed worsened metabolic remodeling and robust transcriptional remodeling highlighted by upregulation of inflammatory genes and downregulation of the mitochondrial structure/function and metabolic processes. Integrated network analysis of metabolomic and RNAseq datasets revealed downregulation of most catabolic energy producing pathways, manifesting in a marked decrease in the energetic state (ie, reduced ATP/ADP, PCr/ATP). Cardiomyocyte ultrastructure analysis revealed decreased mitochondrial area, size, and cristae density, as well as increased lipid droplet content in HFpEF hearts. Impaired mitochondrial function was demonstrated by decreased substrate-mediated respiration and dysregulated calcium handling. Collectively, the integrated omics approach applied here provides a framework to uncover novel genes, metabolites, and pathways underlying HFpEF, with an emphasis on mitochondrial energy metabolism as a potential interventional target
Evaluation of the combination lenvatinib and pembrolizumab in endometrial cancer; a real world multi-institutional review of practice patterns, efficacy and tolerability
No full textObjective: KEYNOTE-775 defined lenvatinib/pembrolizumab as the new standard-of-care for patients with proficient mismatch repair (pMMR) recurrent EC. However, the regimen required dose reductions in 66.5 % of participants and the generalizability of these results was uncertain. We conducted an observational study to determine the prescribing patterns, outcomes and side effects in a real-world setting. Methods: A national multidisciplinary consortium was utilized to study treatment patterns of patients with advanced/recurrent EC treated with lenvatinib/pembrolizumab from 2019 through 2022. Treatment decisions were based on the physician\u27s recommendation. Results: 188 patients across 14 institutions were included. Histologic subtypes were 33 % endometrioid, 41 % serous, 9.6 % mixed, 10.1 % carcinosarcoma, and 2.1 % clear cell. 85.6 % were pMMR and 5.3 % were dMMR. Lenvatinib starting dose was 20 mg in 19.7 %, 18 mg in 14.9 %, 14 mg in 47.3 %, and 10 mg in 18.1 %. Median dose intensity of lenvatinib was 14 mg. Pembrolizumab dosing was 200 mg Q3W in 94.1 %. Grade ≥ 3 adverse events (AE) rates related to lenvatinib were similar across starting doses: 20 mg (13.5 %), 18 mg (17.9 %), 14 mg (7.9 %), 10 mg (17.6 %) (p = 0.31). Response rates in relation to lenvatinib starting dose were 20 mg (27 %), 18 mg (35.7 %), 14 mg (39.3 %), 10 mg (44.1 %) (p = 0.50). In relation to lenvatinib starting dose, PFS, OS and duration of therapy were not statistically different. Response rates (p = 0.24), PFS (p = 0.66) & OS (p = 0.22) were similar in White and Black patients. Conclusions: In a real-world analysis, the predominant starting dose was 14 mg lenvatinib and 200 mg pembrolizumab. Starting at varying doses does not appear to compromise response rates or survival and no new severe adverse events emerged